Recessive dystrophic epidermolysis bullosa (RDEB) is a severe, monogenic disorder caused by mutations to the type VII collagen gene (COL7A1) on chromosome 3. The mutations deactivate production of a structural protein, type VII collagen protein (C7), that affects skin integrity. The loss of C7 at the dermal-epidermal junction compromises the integrity of the attachment of the epidermis to the dermis, resulting in severe blistering, fibrosis, and a predisposition to squamous cell carcinoma. Non-cutaneous manifestations, including corneal and esophageal lesions, further contribute to a pathogenic state leading to a multi-decade decrease in life expectancy.
Existing treatments for RDEB include palliative bandaging of active wounds and pain management, as well as allogeneic and autologous cellular therapy. Palliation is non-curative, and cellular therapy can include localized injection of type VII collagen-expressing cells and/or systemic infusion of hematopoietic stem/progenitor cells (HSPCs) that repopulate the host with donor-derived cells. Keratinocytes and fibroblasts represent the major C7 producing cells of the skin; however, their poor in vitro proliferative and expansion properties as primary cells limit their therapeutic potential and impact. Mesenchymal stromal/stem cells (MSCs) have been used as a supportive therapy and possess wound migratory potential and the ability to actively participate in, as well as to orchestrate, healing. But, similar to other primary cells primary, bone marrow-derived MSCs can senesce and lose their beneficial properties with in vitro expansion.
To mediate systemic effects, allogeneic hematopoietic cell transplant (HCT) has been employed. HCT has resulted in significant, but neither uniform nor complete, outcomes. For each modality, the use of allogeneic cells limits efficacy. Locally injected cells appear to persist transiently, likely due to immune clearance, necessitating repeated injections that are limiting in terms of the difficulty in long-term culture/maintenance, surface area able to be treated, and availability of allogeneic cells that can be obtained, archived, and expanded for subsequent injections. HCT can result in graft-versus-host disease that can cause severe side effects.